Cancer typically involves the deregulation of genes that contribute to maintaining the cell cycle or controlling cell proliferation, such as growth factors and their receptors, oncogenes and tumor suppressor genes. The products of many of these genes are expressed on the surface of a wide variety of tumor cells and, hence, were designated tumor-associated antigens (TAA). Recent evidence supports the existence of tumor-associated antigens that are capable of eliciting an immune response, making these molecules a target for vaccine therapy. Because many of these gene products are also expressed in normal cells, albeit at lower levels, many cancer vaccines targeting tumor-associated antigens have proven ineffective due to immunotolerance.
The product of the HER2/neu proto-oncogene (also called c-erbB-2) is a transmembrane TAA that is a member of the epidermal growth factor receptor family. The HER2/neu gene was originally cloned from a rat neuroglioblastoma (Shih et al., Nature 290: 261-264 (1981)) and later isolated and characterized from human cells (Coussens et al., Science 230: 1132-39 (1985); King et al., Science 229: 974-76 (1985)). To date, no simian homologs of HER2/neu are available.
HER2/neu has been further classified as a member of the HER family of receptor tyrosine kinases, which consists of four receptors that participate in cell growth and differentiation. The HER receptors contribute to maintaining normal cell growth by binding growth factor ligands as dimers, thereby initiating intracellular signaling cascades which ultimately result in the activation of genes important in cell growth. Although several ligands have been identified for other members of the HER family, a high affinity ligand for the HER2/neu receptor has yet to be found (Lohrisch and Piccart, Semin. Oncol. 28(6): Suppl. 18: 3-11 (2001)).
Low levels of expression of the HER2/neu transcript and the encoded 185 kD protein were detected in normal adult epithelial cells of various tissues, including the skin and breast, and tissues of the gastrointestinal, reproductive and urinary tracts (Press et al., Oncogene 5: 953-962 (1990)). Higher levels of HER2/neu expression were also detected in the corresponding fetal tissues during embryonic development (Press et al., supra).
HER2/neu is commonly overexpressed or amplified in various malignancies such as carcinomas of the breast, ovary, uterus, colon, and prostate, and adenocarcinomas of the lung (reviewed in Disis and Cheever, Adv. Cancer Research 71: 343-371 (1997)). Such overexpression of HER2/neu correlates with a poor prognosis and a higher relapse rate for cancer patients (Slamon et al., Science 244: 707-712 (1989)).
Many cancer patients suffering from malignancies associated with HER2/neu overexpression have had immune responses against the protein product of the HER2/neu oncogene, thus making HER2/neu an immunological target for the development of cancer therapeutics. An effective vaccine exploiting this immune response to HER2/neu must both enhance this immunity to a level that is protective and/or preventive and overcome self-tolerance.
HER2/neu has been proposed as a target for the development of immunological treatments of different malignancies. Different anti-HER2 monoclonal antibodies have been investigated as therapies for breast cancer, with each antibody demonstrating various levels of success (for discussion, see Yarden, Oncology 61(suppl 2): 1-13 (2001)). Amici et al. (U.S. Pat. No. 6,127,344) disclose a method for inducing immunity against HER2/neu by administering an expression vector comprising the full-length human HER2/neu cDNA functionally linked to the human cytomegalovirus promoter. Cheever and Disis disclose methods for immunizing humans against HER2/neu-associated cancers with HER2 peptides (U.S. Pat. No. 5,846,538). Additionally, HER2/neu peptide-based vaccines have been studied in rodent models (for review, see Disis and Cheever, Advances in Cancer Research 71:343-71 (1997)).
Despite the identification of the HER2/neu clones mentioned above, it would be highly desirable to identify additional mammalian genes encoding HER2/neu to allow for the development of a cancer vaccine which is efficacious and not hindered by self-tolerance.